Type 2 diabetes mellitus (T2D) has an enormous physical and economic impact worldwide. Despite current treatments, T2D often ultimately requires insulin replacement therapy and diminishes the patients'quality of life owing to complications associated with fluctuating glucose and insulin levels. Several polymorphisms affecting pancreatic islet 2-cell function or proliferation likely are responsible for susceptibility to insulin resistance, manifested as a deficiency of insulin secretion and, ultimately, loss of pancreatic islet function and mass. Ways are being sought to improve insulin secretion early on to limit the death of 2-cells and prolong patients'ability to regulate their own insulin levels, obviating or at least delaying the need for insulin injections. The secretion of insulin from 2-cells in pancreatic islets of Langerhans is regulated by numerous ion channels leading to calcium-dependent insulin exocytosis. De- polarization of the 2-cell causes a signaling cascade resulting in insulin release, while re- polarization halts release. The voltage-dependent K+ (Kv) channel Kv2.1, responsible for re- polarizing the 2-cell action potential, is blocked by conjugation to the ubiquitin-like protein SUMO, resulting in insulin release. SENP-1 is a protease that removes SUMO from Kv2.1, allowing the ion channel to re-polarize, thereby preventing insulin secretion. Thus, an inhibitor of SENP-1 is expected to promote insulin secretion from 2-cells. A targeted screen of the SENP1core has been conducted, and two chemical scaffolds have been identified. One of the screening hits inhibited rodent and human 2-cell Kv channels commensurate with an increase in SUMOylated proteins. It is here proposed to extend this initial SENP-1 based search for new drugs to treat T2D by: 1) optimizing the initially identified small molecule SENP1 inhibitors to achieve improved potency and selectivity;2) identifying additional novel SENP1 inhibitors by screening newly acquired compound libraries;and 3) characterizing the ability of selected SENP1 inhibitors to modulate and insulin secretion from 2-cells. In Phase II, selected inhibitor leads will be progressed to pre-clinical development. PUBLIC HEALTH RELEVANCE: Type 2 diabetes mellitus (T2D) has an enormous physical and economic impact worldwide. Despite current treatments, T2D often ultimately requires insulin replacement therapy and diminishes the patients'quality of life owing to complications associated with fluctuating glucose and insulin levels. A therapeutic agent that increases insulin secretion from 2-cells of the pancreas has been a long sought goal. This project aims to develop a molecule that inhibits an enzyme called SENP-1, which normally functions to keep pancreatic islet cells from releasing insulin under physiological conditions. Such an inhibitor would have great promise as an effective therapy for T2D. In the initial phase of the project, previously-identified SENP-1 inhibitors will be improved by changes to their chemical structure and new inhibitors will be found through high throughput screening. The most "drug-like" of these inhibitors will be tested in cells to see whether they have a positive effect on insulin secretion. In Phase II, the best compounds will be put into preclinical development with the ultimate goal of introducing a new and highly effective drug into the market for T2D.